The structure and physical properties of human non-pancreatic secretory phospholipase A.sub.2 (hereinafter called, "sPLA.sub.2 ") has been thoroughly described in two articles, namely, "Cloning and Recombinant Expression of Phospholipase A.sub.2 Present in Rheumatoid Arthritic Synovial Fluid" by Seilhamer, Jeffrey J.; Pruzanski, Waldemar; Vadas Peter; Plant, Shelley; Miller, Judy A.; Kloss, Jean; and Johnson, Lorin K.; The Journal of Biological Chemistry, Vol. 264, No. 10, Issue of Apr. 5, pp. 5335-5338, 1989; and "Structure and Properties of a Human Non-pancreatic Phospholipase A.sub.2 " by Kramer, Ruth M.; Hession, Catherine; Johansen, Berit; Hayes, Gretchen; McGray, Paula; Chow, E. Pingchang; Tizard, Richard; and Pepinsky, R. Blake; The Journal of Biological Chemistry, Vol. 264, No. 10, Issue of Apr. 5, pp. 5768-5775, 1989; the disclosures of which are incorporated herein by reference.
It is believed that sPLA.sub.2 is a rate limiting enzyme in the arachidonic acid cascade which hydrolyzes membrane phospholipids. Thus, it is important to develop compounds which inhibit sPLA.sub.2 mediated release of fatty acids (e.g., arachidonic acid). Such compounds would be of value in general treatment of conditions induced and/or maintained by overproduction of sPLA.sub.2 ; such as septic shock, adult respiratory distress syndrome, pancreatitis, trauma, bronchial asthma, allergic rhinitis, rheumatoid arthritis, and etc.
Indolyl-3 substituted compounds having glyoxylamide functionality are described in U.S. Pat. No. 2,825,734. This patent related to a process for converting glyoxyamides to 3-(2-amino-1-hydroxyethyl)indoles.
U.S. Pat. No. 3,271,416 describes indolyl aliphatic acids as sun screening agents and intermediates. These acids may be --NH.sub.2 substituted (see, definition of M in claim 1) and require 5- or 6- position substitution with nitrogen or sulfur functional groups.
U.S. Pat. No. 2,890,223 and the article "The Synthesis of Tryptamines Related to Serotaonin", by Elliott Shaw, J. Am. Chem. Soc., Vol. 77, 1955, (pp. 4319-4324 describe several amide derivatives of 3-indoleacetic acids. These compounds are used in the preparation of 5-lower alkoxy tryptamines and are stated to have utility for influencing serotonin related functions in the brain.
Selected indole type compounds have been described in the literature for the treatment of arthritic disorders. Thus, U.S. Pat. Nos. 3,196,162; 3,242,162; 3,242,163; and 3,242,193 (see, Col. 3, lines 55-60, Example 56) describe indolyl aliphatic acids together with their related salts, esters, and amides. These compounds are closely related to compounds like indomethacin, have a substituted benzyl group at the 1 position and likely achieve their beneficial action being cyclooxygenase inhibitors.
The article, "Recherches en serie indolique. VI sur tryptamines substituees", by Marc Julia, Jean Igolen and Hanne Igolen, Bull. Soc. Chim. France, 1962, pp. 1060-1068, describes certain indole-3-acetic acid hydrazides and their conversion to tryptamine derivatives.
It is desirable to develop new compounds and treatments for sPLA.sub.2 induced diseases.